title: Biarylpyrazolyl oxadiazole as potent, selective, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity.
abstract: Since the CB1 cannabinoid receptor antagonist 1 (SR141716, rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a pyrazole core coupled with 1,3,4-oxadiazole were synthesized and tested for CB1 receptor binding affinity. Thorough SAR studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole ring led to several novel CB1 antagonists with IC(50) approximately 1 nM for the CB1 receptor binding. Among these analogues, we identified 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole 43c as a promising precandidate for the development as an antiobesity agent.
authors.affiliation: Central Research Laboratories, Green Cross Corporation, 303 Bojeong-dong, Giheung-gu, Yongin 446-770, Korea.
authors.forename: Suk Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Seo
authors.forename: Sung-Han
authors.initials: SH
authors.lastname: Lee
authors.forename: Myung Eun
authors.initials: ME
authors.lastname: Jung
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
authors.forename: Jakyung
authors.initials: J
authors.lastname: Yoo
authors.forename: Hoseop
authors.initials: H
authors.lastname: Yun
authors.forename: Jooran
authors.initials: J
authors.lastname: Na
authors.forename: Suk Youn
authors.initials: SY
authors.lastname: Kang
authors.forename: Kwang-Seop
authors.initials: KS
authors.lastname: Song
authors.forename: Min-ah
authors.initials: MA
authors.lastname: Kim
authors.forename: Chong-Hwan
authors.initials: CH
authors.lastname: Chang
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Jinhwa
authors.initials: J
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D010069:Oxadiazoles; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2